In 2011, the Institute of Medicine published a consensus report entitled "Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research". This contribution documented and highlighted chronic pain as a public health problem. Those committed to improving prescription management strategies for chronic pain treatment, development of new approaches for pain management, and continuing the search for understanding the mechanisms underlying diverse chronic pains have great hope that the IOM emphasis will enable escalated advances in all three areas. The term "chronic pain" is attributed to a national annual burden of "up to 635 billion dollars per year in medical treatment and lost productivity". Not included in this figure is the immeasurable suffering experienced by patients with that chronic pain. The term "chronic pain" is, at best, an umbrella term used loosely to describe a broad spectrum of chronic pains of different characters, intensities, locations, durations, and etiologies (if known). Diverse chronic pains often share common neurological substrates and mechanisms but can also be distinct and/or multifactorial, rendering diagnosis and optimizing treatment challenging.
Opioid medications continue to be considered the most effective approach for treating various and multiple chronic pains. With the elevated consciousness and commitment to controlling pain, introduction of the sustained release opioid formulations in the 1990s and expansion of prescribing of opioids to chronically manage nonmalignant forms of chronic pain, a concurrent expansion in the incidence of the very serious side effects of addiction and respiratory depression arose. Additionally, the expanded use of opioids to manage pain chronically in patients with longer to normal life expectancy yielded new information as to immune-system related side effects and a neuroadaptive response of the sensory system to chronic inhibition of the pain system. Further, in response to chronic exposure to opioids the sensory system responds by establishing a state of hypersensitivity, a phenomenon previously described but less widely appreciated. Through these prescribing practices and neurobiological research it has become clear that long-term opioid pharmaco-therapy and chronic pain both individually and together impact the nervous system in a complex manner. Developing a greater understanding of that interaction is required in order to optimize pain management strategies for specific and multifactorial pain conditions. Until the 1980s, the tools available to study the neurobiology of chronic pain were fairly limited to acute sensory stimulation via reflex withdrawal methods. Our understanding of chronic opioid exposure has been greatly limited to subjects with normal pain thresholds. The need to expand our understanding of how the nervous system of a patient or subject in chronic pain responds to chronic opioid exposure is increasingly appreciated.
Chronic pain is a generic term to describe a complex state of hypersensitivity that arises from physical injuries, inflammation, internal disease or dysfunction, chemical or chemotherapeutic exposures, or unknown sources. The sensory pathways that traverse the peripheral and central nervous systems respond with physical pathological adaptations to such environmental encounters. During the last 25-30 years, the development and introduction of multiple animal models that mimic such conditions have yielded many examples of neuroanatomical and molecular adaptations specifically in the sensory pathways that help to explain the persistence of chronic pain. Similarly, there has been significant analysis of how chronic opioid exposure impacts the central nervous system, particularly in the widely applied models of opioid analgesic tolerance.
Clinically, patients with chronic pain present with a variety of symptoms that include not only hypersensitivity but also dysesthesia and spontaneous, non-elicited pain. These latter two symptoms are generally assessed in patients using verbal report, and for this reason laboratory animal models with face validity that mimic this symptomatology have proven to be more difficult to develop and interpret than reflexive withdrawal models of hypersensitivity. Pertinent to this volume, opioids are particularly useful in relief from spontaneous pain and this symptom is frequently reported to be the more troublesome and disabling component of chronic pain. Progress in developing preclinical models of spontaneous pain is also reviewed within this work when appropriate.
In contrast, there is minimal information as to how the maladapted nervous system with established chronic pain (regardless of etiology) responds to chronic opioid exposure. A limited number of investigators in the 1980s and the early 1990s initiated studies of opioid self-administration or conditioned place preference under conditions of inflammation-induced chronic pain and nerve injury-induced chronic pain. Following that approach, we have similarly assessed the responding of rats (Ewan and Martin) and mice (Wade and Fairbanks) with established chronic pain for opioid reward. Our results together with some of our colleagues represented in this volume (Wade, Koob, Narita, Suzuki) and others support the assertion that subjects with established chronic pain respond to analgesic reinforcers differently than do subjects with normal pain thresholds. Scientific interest and inquiry in the concept that chronic pain results in significant and clinically relevant alterations in addiction-related centers in the brain are escalating. We anticipate that the blending of the fields of chronic pain mechanisms with that of opioid and/or other reinforcing addiction will greatly expand our knowledge as to how chronic pain of differing etiologies does or does not impact a subjects' propensity toward addiction of analgesic substances.
Through this volume, we hope to provide the reader with a valuable summary of the two fields and how best to use the information already gained and the tools available to continue to pursue the knowledge that will aid in managing chronic pain safely and effectively.
We have organized the text into three primary sections:
Part I introduces the defined set of investigations that have blended the standard models of chronic pain and opioid addiction. Fairbanks and Wade summarize the early self-administration and conditioned place preference studies of opioid and non-opioid analgesics in chronic pain models that were initiated in the early 1980s and have continued to be investigated through to the present day.
Part II emphasizes current research that investigates the specific brain regions that may account for alterations in opioid or non-opioid responding in subjects with chronic pain. Ewan and Martin provide a more in-depth description of their recent studies of opioid and non-opioid self-administration under conditions of chronic pain. Additionally, they describe the use of intracranial manipulations in discrete brain regions in subjects with chronic pain as a means to answer the key questions as to which specific brain regions contribute to the clear pattern of alterations in opioid self-administration in subjects with chronic pain. Ghandi, Becker, and Schweinhardt provide a comprehensive consideration of how short-term and long-term pain influence reward processing, specifically featuring the intersection of cerebral regions that are involved in both pain processing and reward. Narita and colleagues describe specific molecular and neurobiological changes in the mesolimbic system under conditions of chronic pain that may account for altered opioid responding.
Part III focuses on methodological information important to the blend of chronic pain and addiction modeling. Wade, Koob, and Vendrusculo describe the models used for sensory assessment and to induce chronic pain states as well as addiction. Fairbanks and Peterson review and summarize the biopharmaceutical aspects that distinguish eight widely prescribed opioid analgesics as well as a review of the relevance of blood-brain barrier transport to opioid pharmacology.
Part IV concludes the collection with commentaries on the clinical impact of the expanded use of prescription opioids. Lisa Schrott focuses on the impact of prenatal exposure to prescription opioids with an emphasis on the impact on cognition and memory identified through animal modeling of prenatal opioid exposure. Scott Strassels summarizes three primary challenges associated with opioid pain management: opioid-induced hyperalgesia, how to best measure clinical outcomes, and challenges and opportunities associated with the development of prescription monitoring programs.
It is our hope that readers will find this collection informative regarding the current state of knowledge that has been gained from combining animal modeling of addiction and chronic pain. It is important to expand our knowledge of how subjects in diverse states of chronic pain respond to opioid as well as non-opioid classes of analgesic mediations. Minneapolis, MN, USA Carolyn A. Fairbanks; Winston-Salem, NC, USA Thomas J. Martin

Part I Introduction

1 Opioid and Non-Opioid Drug Responding Under States of Chronic Pain: A Timeline Spanning 1980 to Present Day 3

Carrie L. Wade and Carolyn A. Fairbanks

Part II Basic Science

2 Opioid Self-Administration in the Presence of Chronic Pain: Analgesia or Addiction? 17

Eric E. Ewan and Thomas J. Martin

3 The Influence of Pain on Reward Processing: Current Literature and Prospects 31

Wiebke Gandhi, Susanne Becker, and Petra Schweinhardt

4 Chronic Pain Stimuli Downregulate Mesolimbic Dopaminergic Transmission: Possible Mechanism of the Suppression of Opioid Reward 49

Minoru Narita, Keiichi Niikura, Akira Yamashita, Daigo Ikegami, Naoko Kuzumaki, Michiko Narita, and Tsutomu Suzuki

Part III Methods

5 Drug Addiction and Chronic Pain: A Review of Animal Models 61

Carrie L. Wade, George F. Koob, and Leandro F. Vendruscolo

6 Biopharmaceutical Considerations of Opioid Analgesics in Models of Self-Administration: Review and Summary 81

Carolyn A. Fairbanks and Cristina D. Peterson.

Part IV Clinical Perspectives

7 Prenatal Exposure to Opioids 111

Lisa M. Schrott

8 Opioids in an Evidence-Based World 119

Scott A. Strassels

Index 129

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